PROJECT SUMMARY/ABSTRACT Osteogenesis Imperfecta (OI) is the most commonly inherited form of brittle bone disease, which is characterized by a wide-ranging severity from mild phenotypes to severe congenital lethality. OI is commonly caused by mutations in the two genes that encode type I collagen but recent studies have shed light on several recessive OI cases resulting from abnormalities in collagen synthesis, secretion and/or folding. One of the most well-studied forms of recessive is caused by mutations in the prolyl 3- hydroxylase 1 (P3H1) complex (consisting of cartilage associated protein [CRTAP], P3H1 and cyclophilin B [CypB]), which are essential for prolyl hydroxylation of type I procollagen, and failure to do so results in defective collagen cross-linking. In addition, we and others have recently identified several families that developed progressive bone fragility and congenital joint contractures (i.e. recessive OI and Bruck syndrome) due to loss-of-function mutations in FK506 binding protein 10, 65 KDa!(FKBP10), which encodes the ER-chaperone protein FKBP65. To understand the function of FKBP10, our laboratory previously generated Fkbp10-null mice which displayed connective tissue abnormalities and reduced collagen cross-linking. While the global Fkbp10 knockout mice phenocopied certain aspects of the human disease condition, they unexpectedly resulted in embryonic lethality. Therefore, the goal of this proposal is to elucidate the tissue specific functions of FKBP10 in regulating tendon homeostasis. In other types of recessive OI, the biochemical modifications of collagen are altered, in particular by P3H1. Additionally, studies on Crtap knockout mice have revealed that collagen abnormalities alter cell signaling, which is the predominant mechanism underlying disease. I hypothesize that tissue-specific loss of FKBP10 negatively affects type I collagen cross-linking and alters cell signaling within the tissue microenvironment, ultimately resulting in OI and Bruck syndrome. I aim to test this hypothesis by determining the effects of tissue specific Fkbp10 removal on the molecular, biochemical, and biomechanical properties of tendons. The experiments proposed in this training plan is critical for establishing both unique and common mechanisms of disease, which may provide potential therapeutic targets for patients with OI and Bruck syndrome as well as other types of OI cases. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is the recipient organization of this fellowship because recessive OI and Bruck syndrome are characterized by abnormalities in both skeletal and connective tissues.